This invention relates to protease inhibitors, and particularly to transition state analogs.
Transition state analogs, compounds which are thought to resemble the substrates of enzymes, are thought to bind more tightly to the enzymes than the substrates themselves. Transition state analogs form complexes with enzymes at their catalytic sites.
Baugh et al. (Proteinases and Tumor Invasion ed. Strauli et al., Raven Press, N.Y., 1980, p. 165) state that transition state analogs containing boronic acid moieties or aldehydes form tetrahedral adducts with serine proteases and are thus good inhibitors of these enzymes. Further, they state that some peptide aldehydes have been synthetically prepared, that most are of microbial origin, and that "it would appear that changing the R-group [of synthetic peptides] to satisfy the specific requirements of a given protease should result in both potent and specific inhibitors." They also state that transition state analogs containing cyclic ester moieties have been used to inhibit chymotrypsin and that "variations thereof may become useful as inhibitors of cathepsin G."
Yoshimoto et al. (J. Biochem .98: 975, 1985) describe prolyl endopeptidase inhibitors containing a protinal moiety. These inhibitors appear to act non-competitively.
Shenvi et al., U.S. Pat. No. 4,499,082, describe peptides having an .alpha.-amino boronic acid residue. These peptides are reversible inhibitors of elastase. They have the structureal formula ##STR6## where R.sub.2 is an alkyl group of one to six carbons which may have an aromatic substituent or an in-chain bivalent group.